Enzalutamide was approved for the treatment of metastatic castration resistant prostate cancer (CRPC). Despite these advances that provide survival gains, there is still no cure for CRPC. Resistance to enzalutamide occurs frequently and the mechanisms are incompletely understood. Hence, dissecting the specific adaptive/resistant pathways that are responsible for drug resistance in CRPC and identifying novel strategies targeting these pathways will dramatically impact the care of men with CRPC. Lin28, a RNA binding protein, acts as an oncogene inducing cell proliferation and transformation. Lin28 suppresses let-7, a miRNA involved in suppressing androgen signaling. Our preliminary data suggest that Lin28 promotes castration resistant prostate cancer progression and is associated with resistance to androgen ablation treatment. Lin28 is upregulated in prostate cancer and its expression correlates with advanced tumor stage. Together, these studies underscore the importance of Lin28 in promoting prostate cancer progression and resistance to enzalutamide, suggesting that targeting Lin28 may provide novel therapeutic opportunities for prostate cancer. This proposal will determine the roles of Lin28 in resistance to enzalutamide, and explore the potential of targeting Lin28 to overcome resistance. The specific aims of this proposal are: 1. Examine the roles of Lin28 in the development of resistance to enzalutamide. 2. Determine molecular mechanisms underlying Lin28-mediated resistance to enzalutamide. 3. Evaluate targeting Lin28 to overcome resistance to enzalutamide treatment. The proposed studies will identify and characterize a novel resistance mechanism involving Lin28 and evaluate targeting Lin28 to overcome resistance to enzalutamide treatment.